DEFINITION
A short protein description with the molecular wheight, isoforms, etc...
Use, when available, the link to Wikipedia (Es Trypsin)
CHEMICAL STRUCTURE AND IMAGES
When relevant for the function
- Primary structure
- Secondary structure
- Tertiary structure
- Quaternary structure
Comparison of SMAD4 and SMAD7 (inhibitor)
SMAD7 has
- Methionine, Isoleucine, Histidine
- Glycine, Arginine, Leucine
SYNTHESIS AND TURNOVER
mRNA synthesis
protein synthesis
post-translational modifications
smad7 valproic acid butyrate
degradation
SMAD7 is synthesized in high glycine and inhibited by methylation (high serine)
Methylation of Smad6 by protein arginine N-methyltransferase 1. 2006
FEBS Lett. 2006 Dec 11;580(28-29):6603-11.
Signal transduction pathways utilize posttranslational modifications to regulate the activity of their components in a temporal-spatial and efficient fashion. Arginine methylation is one of the posttranslational modifications that can result in monomethylated-, asymmetric dimethylated- and/or symmetric dimethylated-arginine residues in proteins. Here we demonstrate that inhibitory-Smads (Smad6 and Smad7), but not receptor-regulated- (R-)Smads and the common-partner Smad4, can be methylated by protein arginine N-methyltransferase (PRMT)1. Using mass-spectrometric analysis, we found that PRMT1 dimethylates arginine(74) (Arg(74)) in mouse Smad6. PRMT1 interacts with the N-terminal domain of Smad6 in which Arg(74) residue is located. Assays examined so far have shown no significant differences between the functions of Smad6 and those of methylation-defective Smad6 (Smad6R74A). Both wild-type and Smad6R74A were equally efficient in blocking BMP-induced growth arrest upon their ectopic expression in HS-72 mouse B-cell hybridoma cells.
CELLULAR FUNCTIONS
cellular localization,
1. FUNCTION: Antagonist of signaling by TGF-beta (transforming growth factor) type 1 receptor superfamily members; has been shown to inhibit TGF-beta (Transforming growth factor) and activin signaling by associating with their receptors thus preventing SMAD2 access. Functions as an adapter to recruit SMURF2 to the TGF-beta receptor complex. Also acts by recruiting the PPP1R15A- PP1 complex to TGFBR1, which promotes its dephosphorylation.
2. SUBUNIT: Interacts with TGF-beta type I receptor. Interacts with COPS5. Interacts with NEDD4L. Interacts with STAMBP. Interacts with RNF111, AXIN1 and AXIN2. Interacts with PPP1R15A. Interacts (via MH2 domain) with EP300. Interacts with SMURF2.
3. SUBCELLULAR LOCATION: Nucleus. Cytoplasm. Note=Interaction with NEDD4L or RNF111 induces translocation from the nucleus to the cytoplasm.
4. TISSUE SPECIFICITY: Ubiquitous with higher expression in the lung and vascular endothelium.
5. INDUCTION: By TGF-beta.
6. PTM: Phosphorylation on Ser-249 does not affect its stability, nuclear localization or inhibitory function in TGFB signaling; however it affects its ability to regulate transcription (By similarity).
7. PTM: Polyubiquitinated by RNF111, which is enhanced by AXIN1 and promotes proteasomal degradation. In response to TGF-beta, ubiquitinated by SMURF1; which promotes its degradation.
8. PTM: Acetylation prevents ubiquitination and degradation mediated by SMURF1.
9. DISEASE: Genetic variations in SMAD7 influence susceptibility to colorectal cancer type 3 (CRCS3) [MIM:612229]. Colorectal cancer consists of tumors or cancer of either the colon or rectum or both. Cancers of the large intestine are the second most common form of cancer found in males and females. Symptoms include rectal bleeding, occult blood in stools, bowel obstruction and weight loss. Treatment is based largely on the extent of cancer penetration into the intestinal wall. Surgical cures are possible if the malignancy is confined to the intestine. Risk can be reduced when following a diet which is low in fat and high in fiber.
10. SIMILARITY: Belongs to the dwarfin/SMAD family.
11. SIMILARITY: Contains 1 MH1 (MAD homology 1) domain.
12. SIMILARITY: Contains 1 MH2 (MAD homology 2) domain.
biological function
It behaves as an oncogene. High activity is associated with cancer growth
SMAD7 controls iron metabolism as a potent inhibitor of hepcidin expression. 2010
Blood. 2010 Apr 1;115(13):2657-65. Epub 2009 Dec 29.
Hepcidin is the master regulatory hormone of systemic iron metabolism. Hepcidin deficiency causes common iron overload syndromes whereas its overexpression is responsible for microcytic anemias. Hepcidin transcription is activated by the bone morphogenetic protein (BMP) and the inflammatory JAK-STAT pathways, whereas comparatively little is known about how hepcidin expression is inhibited. By using high-throughput siRNA screening we identified SMAD7 as a potent hepcidin suppressor. SMAD7 is an inhibitory SMAD protein that mediates a negative feedback loop to both transforming growth factor-beta and BMP signaling and that recently was shown to be coregulated with hepcidin via SMAD4 in response to altered iron availability in vivo. We show that SMAD7 is coregulated with hepcidin by BMPs in primary murine hepatocytes and that SMAD7 overexpression completely abolishes hepcidin activation by BMPs and transforming growth factor-beta. We identify a distinct SMAD regulatory motif (GTCAAGAC) within the hepcidin promoter involved in SMAD7-dependent hepcidin suppression, demonstrating that SMAD7 does not simply antagonize the previously reported hemojuvelin/BMP-responsive elements. This work identifies a potent inhibitory factor for hepcidin expression and uncovers a negative feedback pathway for hepcidin regulation, providing insight into a mechanism how hepcidin expression may be limited to avoid iron deficiency.
- Enzymes
- Cell signaling and Ligand transport
- Structural proteins
REGULATION
Regulation of TGF-b signaling by Smad7 2009
DIAGNOSTIC USE
J Natl Cancer Inst. 2005 Dec 7;97(23):1734-46.
Effect of Smad7 expression on metastasis of mouse mammary carcinoma JygMC cells.
Azuma H, Ehata S, Miyazaki H, Watabe T, Maruyama O, Imamura T, Sakamoto T, Kiyama S, Kiyama Y, Ubai T, Inamoto T, Takahara S, Itoh Y, Otsuki Y, Katsuoka Y, Miyazono K, Horie S.
Department of Urology, Osaka Medical College, Takatsuki, Osaka, Japan.
Comment in:
* J Natl Cancer Inst. 2005 Dec 7;97(23):1714-5.
Abstract
BACKGROUND: Transforming growth factor beta (TGF-beta) facilitates metastasis during the advanced stages of cancer. Smad6, Smad7, and c-Ski block signaling by the TGF-beta superfamily proteins through different modes of action. We used adenovirus-mediated gene transfer of these natural inhibitors in a mouse model of breast cancer to examine the roles of TGF-beta superfamily signaling in tumor growth and metastasis. METHODS: We systemically administered, by intravenous injection, adenoviruses (AdCMV) containing the mouse cDNAs for Smad7, Smad6, c-Ski, the c-Ski mutant c-Ski (ARPG), or LacZ (control) to nude mice (>19 mice/group) bearing tumors derived from mouse mammary carcinoma JygMC cells, which spontaneously metastasize to lung and liver, and examined their effects on survival and metastasis. High-throughput western blotting analysis was used to examine the expression levels for 47 signal transduction proteins in JygMC cells and primary tumors. We also investigated the proliferation, migration, and invasion of JygMC cells that stably overexpressed Smad6 or Smad7. Nonparametric comparisons were done by Kruskal-Wallis H statistic and Wilcoxon's rank sum tests. Parametric comparisons were done by one-way analysis of variance or two-sided unpaired Student's t tests. All statistical tests were two-sided. RESULTS: Control mice bearing tumors derived from JygMC cells showed many metastases to the lung and liver; all animals died by 50 days after cell inoculation. By contrast, mice treated with AdCMV-Smad7 or AdCMV-c-Ski demonstrated a dramatic decrease in metastasis and statistically significantly longer survival than control mice (Smad7 versus LacZ: medium survival = 55 days versus 41 days, difference = 14 days [95% confidence interval {CI} = 6 days to 22 days], P < .001), whereas mice treated with AdCMV-Smad6 or AdCMV-c-Ski (ARPG) did not. Expression of Smad7 in JygMC cells was associated with increased expression of major components of adherens and tight junctions, including E-cadherin, decreased expression of N-cadherin, and decreases in the migratory and invasive abilities of the JygMC cells. CONCLUSION: Smad7 inhibits metastasis, possibly by regulating cell-cell adhesion. Systemic expression of Smad7 may be a novel strategy for the prevention of metastasis of advanced cancers.
Methylation of Smad6 by protein arginine N-methyltransferase 1 2006
